Cancer is a serious health issue all around the world. Cancer affects people at all ages, even fetuses. As reported by the World Health Organization in 2007, cancer causes about 13% of all deaths. About 7.6 million people died from cancer in the world during 2007.
Cancer is a disease resulting from an abnormal growth of tissue. Certain cancers have the potential to invade into local tissues and also metastasize to distant organs. The disease can develop in a wide variety of different organs, tissues and cell types. Therefore, the term “cancer” refers to a collection of over a thousand different diseases.
Despite recent advancements made in treating cancers, it is often observed that with very few exceptions, a cancer treatment fails to cure a patient. One of the main causes of failure in the treatment of cancer is the development of drug resistance by the cancer cells. In other words, after several cycles of chemotherapy, some tumor cells become resistant to the chemotherapeutic agent, which results in a loss of response to further therapy. This is a very serious problem that may lead to recurrence of disease or even death.
In these cases, tumors can be resistant to a variety of anticancer drugs with different structures and mechanism of action. Mechanisms of resistance extrinsic to cancer cells include altered pharmacokinetics, poor drug penetration through the extracellular matrix, cell adhesion and increased intratumoral hydrostatic pressure. Intrinsic cellular resistance further decreases the effectiveness of chemotherapy. Although there are several different intrinsic cellular mechanisms associated with the development of drug resistance, a common cause is believed to be overexpression of a plasma membrane glycoprotein (Pgp).
Pgp is the best known and most important mediator of drug resistance. This gene product belongs to the ABC (ATP binding cassette) superfamily of transporter proteins, and it acts as an energy-dependent drug efflux pump, preventing adequate intracellular accumulation of a broad range of cytotoxic drugs for cell kill. Pgp expression, frequently detected in the solid, hematologic cancers found in humans, as well as recently reported cancer stem cells, is a marker of chemoresistance or decreased survival in leukemia, lymphoma, osteosarcoma, small-cell lung cancer, ovarian cancer, breast cancer, and many other malignancies. Innate or acquired expression of Pgp, therefore, is a major problem in cancer chemotherapy.
Numerous efforts have been made in the art to overcome drug resistance. A broad range of compounds that interact with Pgp and block drug efflux have been reported to reverse the drug resistance phenotype. Unfortunately, it has been reported that the majority of these chemosensitizers lack in vivo activity due to problems associated with maintaining active doses without causing serious side effects. For instance, for verapamil, a calcium channel blocker, the doses required to modify drug resistance are associated with cardiac toxicity. Another example is CsA, which has been found to exert immunosuppressive effects and nephrotoxicity. Also, it was reported that PSC 833 causes cerebellar ataxia and hyperbilirubinemia toxicities. In addition, many of these Pgp inhibitors are compounds developed for other clinical uses and therefore lacked sufficient potency and/or specificity. Many of these Pgp inhibitors exhibit non-target-related toxicities that compromise the achievement of therapeutic exposures.
Therefore, there is an unmet clinical need for development of potent and selective drug resistance inhibitors to reduce the severity or incidence of the drug resistance in a cancer chemotherapy.